The number of patients with diabetes mellitus has been increasing steadily owing to the recent change in the lifestyle. According to the research done in 1997 in Japan, it has been speculated that the number of people strongly-speculated as having diabetic mellitus is 6.9 million, and the number of people who can not be deniable the possibility of diabetes mellitus is 6.8 million. Most of the patients with diabetes mellitus in Japan are classified into type 2 diabetes mellitus, wherein the basal pathological conditions thereof are the reduced output of insulin and the insulin resistance, and medicaments against to each condition have been developed.
Although sulfonylurea (SU) agents, which is known from of old, have widely been used for improving the reduced output of insulin, the agents are known to have a risk of hypoglycemia as a serious side effect, and further to be apt to cause obesity.
On the other hand, thiazolidinedione agents are known as an insulin resistance improving agent.
Troglitazone was first put on market as a thiazolidinedione agent, but its sale was discontinued due to a serious hepatic damage. In Japan, pioglitazone has been clinically used at the present, but the heart failure due to the increase in circulating plasma volume was reported as a serious side effect thereof, and hence, Urgent Safety Information on pioglitazone was issued on October, 2000, which announced that pioglitazone needs careful attention to heart failure and edema. As to rosiglitazone, which has been widely used in Europe and the U.S., there are reported side effects such as infection of upper respiratory tract, anemia, edema, weight gain, etc. Thus, any thiazolidinedione agent having no concern regarding hepatic damage or side effects on the cardiovascular system has not been put on the market yet.
Thiazolidinedione agents are thought to exhibit anti-diabetic activity by activating PPARγ. It is known that PPAR has subtypes such as α, γ, δ (β), etc. Fibrate agents (e.g., clofibrate, fenofibrate, etc.), which are used as an agent for treating hyperlipemia, are considered to exhibit their pharmacological activities by activating PPARα. It has recently been reported that the insulin resistance is improved by administering a PPARα activator to animal models (cf., Journal of Biological Chemistry, vol. 275, p 16638, 2000), and there is a growing possibility where PPARα activators may show an effectiveness against diabetes mellitus as well as hyperlipidemia.
Many of compounds activating PPARγ or both PPARα and PPARγ such as isoxazolidindiones are reported other than thiazolidinedione agents (cf., Journal of Medicinal Chemistry, 43, p. 527, 2000), but the efficacy and safety thereof in the clinical field are not confirmed yet. At the present, PPARα agonists, PPARγ agonists, PPARα/γ agonists or PPARα/γ activation regulators having a good antidiabetic activity, are useful for treating or preventing metabolic diseases such as hyperlipemia, arteriosclerosis or metabolic syndrome and having high safety have been desired.
Many diabetic agents called PPARγ activation regulators (modulators, partial agonists) have been recently reported (c.f., Bioorganic & Medicinal Chemistry Letters, Vol. 15, p357-362 (2005), and European Journal of Pharmacology, p273-281 (2004)). There is suggested a possibility that these agents do not show side effects such as weight gain, edema or increase in heart weight observed in PPARγ full agonist such as pioglitazone or rosiglitazone, and have a good antidiabetic activity. The medicament having partial activity of PPARγhas been greatly expected to become a diabetic agent with high safety.
In addition, diabetic medicines having a pyrrole group in its structure have are known (cf, JP-A-2002-121186, WO 02/085851, WO 2004/048341), but the efficacy and safety thereof in the clinical field are not reported yet.